Processes for preparing quinoline compounds and pharmaceutical compositions containing such compounds

ABSTRACT

The present invention is directed to processes for making and compositions containing quinolines such as formula I or pharmaceutically acceptable salts thereof wherein: X1 is H, Br, Cl, or X2 is H, Br, Cl, or n1 is 1-2; and n2 is 1-2.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. Ser. No.15/348,716, filed Nov. 10, 2016, which is a divisional application ofU.S. Ser. No. 13/984,559, filed Mar. 20, 2014, which claims priorityunder 35 U.S.C. § 371 to Patent Cooperation Treaty applicationPCT/US2012/024591, filed Feb. 10, 2012, which claims the benefit of U.S. provisional application No. 61/441,520, filed Feb. 10, 2011, and U.S. provisional application No. 61/441,527, filed Feb. 10, 2011, theentire contents of which are incorporated herein by reference.

FIELD OF THE INVENTION

This disclosure relates to processes for preparing compounds useful formodulating protein kinase enzymatic activity. More specifically, thisdisclosure relates to processes for preparing quinolines that are usefulfor modulating cellular activities such as proliferation,differentiation, programmed cell death, migration, and chemo-invasionand to pharmaceutical compositions containing such compounds.

BACKGROUND OF THE INVENTION

Traditionally, dramatic improvements in the treatment of cancer areassociated with identification of therapeutic agents acting throughnovel mechanisms. One mechanism that can be exploited in cancertreatment is the modulation of protein kinase activity because signaltransduction through protein kinase activation is responsible for manyof the characteristics of tumor cells. Protein kinase signaltransduction is of particular relevance in, for example, renal, gastric,head and neck, lung, breast, prostate, and colorectal cancers;hepatocellular carcinoma; as well as in the growth and proliferation ofbrain tumor cells.

Protein kinases can be categorized as receptor type or non-receptortype. Receptor-type tyrosine kinases are comprised of a large number oftransmembrane receptors with diverse biological activity. For a detaileddiscussion of the receptor-type tyrosine kinases, see Plowman et al.,DN&P 7(6): 334-339, 1994. Since protein kinases and their ligands playcritical roles in various cellular activities, deregulation of proteinkinase enzymatic activity can lead to altered cellular properties, suchas uncontrolled cell growth associated with cancer. In addition tooncological indications, altered kinase signaling is implicated innumerous other pathological diseases, including, for example,immunological disorders, cardiovascular diseases, inflammatory diseases,and degenerative diseases. Therefore, protein kinases are attractivetargets for small molecule drug discovery. Particularly attractivetargets for small-molecule modulation with respect to antiangiogenic andantiproliferative activity include receptor type tyrosine kinases c-Met,KDR, c-Kit, Axl, flt-3, and flt-4.

The kinase c-Met is the prototypic member of a subfamily ofheterodimeric receptor tyrosine kinases (RTKs) which include Met, Ron,and Sea. The endogenous ligand for c-Met is the hepatocyte growth factor(HOF), a potent inducer of angiogenesis. Binding of HGF to c-Met inducesactivation of the receptor via autophosphozylation, resulting in anincrease of receptor dependent signaling, which promotes cell growth andinvasion. Anti-HGF antibodies or HGF antagonists have been shown toinhibit tumor metastasis in vivo (See: Maulik et al Cytokine & GrowthFactor Reviews 2002 13, 41-59). c-Met overexpression has beendemonstrated on a wide variety of tumor types including breast, colon,renal, lung, squamous cell myeloid leukemia, hemangiomas, melanomas,astrocytomas, and glioblastomas. Additionally, activating mutations inthe kinase domain of c-Met have been identified in hereditary andsporadic renal papilloma and squamous cell carcinoma. (See, e.g., Mauliket al., Cytokine & growth Factor reviews 2002 13, 41-59; Longati et al.,Curr Drug Targets 2001, 2, 41-55; Funakoshi et al., Clinics Chimica Acta2003 1-23).

Inhibition of epidermal growth factor (EGF), vascular endothelial growthfactor (VEGF), and ephrin signal transduction will prevent cellproliferation and angiogenesis, two key cellular processes needed fortumor growth and survival (Matter A., Drug Disc. Technol. 2001 6,1005-1024). Kinase KDR (refers to kinase insert domain receptor tyrosinekinase) and flt-4 (fins-like tyrosine kinase-4) are both VEGF receptors.Inhibition of EGF, VEGF, and ephrin signal transduction will preventcell proliferation and angiogenesis, two key cellular processes neededfor tumor growth and survival (Matter A. Drug Disc. Technol. 2001 6,1005-1024). EGF and VEGF receptors are desirable targets for smallmolecule inhibition. All members of the VEGF family stimulate cellularresponses by binding to tyrosine kinase receptors (the VEGFRs) on thecell surface, causing them to dimerize and become activated throughtransphosphorylation. The VEGF receptors have an extracellular portionwith immunoglobulin-like domains, a single transmembrane spanningregion, and an intracellular portion containing a split tyrosine-kinasedomain. VEGF binds to VEGFR-1 and VEGFR-2. VEGFR-2 is known to mediatealmost all of the known cellular responses to VEGF.

Kinase c-Kit (also called stem cell factor receptor or steel factorreceptor) is a type 3 receptor tyrosine kinase (RTK) belonging to theplatelet-derived growth factor receptor subfamily. Overexpression ofc-Kit and c-Kit ligand has been described in variety of human diseases,including human gastrointestinal stromal tumors, mastocytosis, germ celltumors, acute myeloid leukemia (AML), NK lymphoma, small-cell lungcancer, neuroblastomas, gynecological tumors, and colon carcinoma.Moreover, elevated expression of c-Kit may also relate to thedevelopment of neoplasia associated with neurofibromatosis type 1(NF-1), mesenchymal tumors GISTs, and mast cell disease, as well asother disorders associated with activated c-Kit.

Kinase Flt-3 (fins-like tyrosine kinase-3) is constitutively activatedvia mutation, either in the juxtamembrane region or in the activationloop of the kinase domain, in a large proportion of patients with AML(Reilly, Leuk. Lymphoma, 2003, 44: 1-7).

Small-molecule compounds that specifically inhibit, regulate, and/ormodulate the signal transduction of kinases, such as c-Met, VEGFR2, KDR,c-Kit, Axl, flt-3, and At-4 described above, are particularly desirableas a means to treat or prevent disease states associated with abnormalcell proliferation and angiogenesis. One such small-molecule is compoundIA, which has the chemical structure:

WO2005/030140 describes the synthesis of compound IA (Table 2, Compound12, Example 48) and also discloses the therapeutic activity of thismolecule to inhibit, regulate, and/or modulate the signal transductionof kinases (Assays, Table 4, entry 289), the entire contents of which isincorporated herein by reference.

Although therapeutic efficacy is the primary concern for a therapeuticagent, the pharmaceutical composition can be equally important to itsdevelopment. Generally, the chug developer endeavors to discover apharmaceutical composition that possesses desirable properties, such assatisfactory water-solubility (including rate of dissolution), storagestability, hygroscopicity, and reproducibility, all of which can impactthe processability, manufacture, and/or bioavailability of the drug.

Accordingly, there is a need for the discovery of new processes formaking quinolines such as compound IA that minimize the formation ofundesirable process contaminants or byproducts. There is also a need fornew pharmaceutical compositions containing quinolines such as compoundIA that are essentially free of process byproducts.

SUMMARY OF TEE INVENTION

These and other needs are met by the present disclosure, which isdirected to processes for making and compositions containing quinolinesor pharmaceutically acceptable salts thereof.

In one aspect, the disclosure relates to processes for preparing acompound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

X¹ is H, Br, Cl, or F;

X² is H, Br, Cl, or F;

n1 is 1-2; and

n2 is 1-2.

Intermediates useful in preparing the above compounds are alsodisclosed.

The compounds of formula I are useful as protein kinase modulators, andthey inhibit various protein kinases including Ret and c-Met.

In another aspect, the disclosure provides a process for preparingcompound IB:

from compound IA:comprising:

-   -   (a) heating and agitating a mixture comprising compound IA and        L-malic acid, methylethyl ketone, and water,    -   (b) cooling the mixture;    -   (c) vacuum distilling the mixture successively; and    -   (d) isolating the compound of IB by filtration.

In another aspect, the disclosure provides a process for preparingcompound IB:

from compound IA:comprising:

-   -   (a) heating and agitating a mixture comprising compound IA and        L-malic acid, methylethyl ketone, and water;    -   (b) cooling the mixture;    -   (c) seeding the mixture with compound IB;    -   (d) vacuum distilling the mixture; and    -   (e) isolating compound IB by filtration.

In another aspect, the disclosure provides compound I, IA, or IB admixedwith less than 100 ppm 6,7-dimethoxy-quinoline-4-ol, the structure ofwhich is

In another aspect, the disclosure provides pharmaceutical compositionscontaining the compound of formula I, compound IA, or compound IB fororal administration.

In another aspect, the disclosure provides a pharmaceutical tabletcomposition according to Table 1.

TABLE 1 Ingredient % w/w Compound I 31.68 Microcrystalline Cellulose38.85 (MCC) (Avicel PH102) Lactose anhydrous 60M 19.42 HydroxypropylCellulose, EXF 3.00 Croscarmellose Sodium 3.00 Total Intra-granular95.95 Silicon dioxide, Colloidal PWD 0.30 Croscarmellose Sodium 3.00Magnesium Stearate 0.75 Total 100.00

In another aspect, the disclosure provides a pharmaceutical tabletcomposition according to Table 2.

TABLE 2 Ingredient (% w/w) Compound I 25.0-33.3 MicrocrystallineCellulose, NF q.s Hydroxypropyl Cellulose, NF 3 Poloxamer, NF 0-3Croscarmellose Sodium, NF 6.0 Colloidal Silicon Dioxide, NF 0.5Magnesium Stearate, NF 0.5-1.0 Total 100

In another aspect, the disclosure provides a pharmaceutical tabletcomposition according to Table 2A.

TABLE 2A Ingredient % w/w Compound IB (10% drug 12.67 load as CompoundIA) MCC 51.52 Lactose 25.76 Hydroxypropyl cellulose 3.0 CroscarmelloseSodium 6.0 Colloidal Silicon Dioxide 0.3 Magnesium Stearate 0.75 Total100

In another aspect, the disclosure provides a pharmaceutical capsulecomposition according to Table 3.

TABLE 3 mg/unit Ingredient dose Compound IB (10% drug 25 load asCompound IA) Silicified Microcrystalline 196.75 Cellulose Croscarmellosesodium 12.5 Sodium starch glycolate 12.5 Fumed Silica 0.75 Stearic acid2.5 Total Fill Weight 250

In another aspect, the disclosure provides a pharmaceutical capsulecomposition according to Table 4.

TABLE 4 mg/unit Ingredient dose Compound IB (50% drug 100 load asCompound IA) Silicified Microcrystalline 75.40 Cellulose Croscarmellosesodium 10.00 Sodium Starch Glycolate 10.00 Fumed silica 0.6 Stearic Acid4.0 Total Fill Weight 200

In another aspect, the disclosure provides a pharmaceutical capsulecomposition according to Table 5, wherein the IB weight equivalents areprovided.

TABLE 5 mg/unit dose Ingredient 50 mg Compound IB 63.35 MicrocrystallineCellulose 95.39 Croscarmellose sodium 9.05 Sodium starch glycolate 9.05Fumed Silica 0.54 Stearic acid 3.62 Total Fill Weight 181.00

In another aspect, the disclosure provides a pharmaceutical capsulecomposition according to Table 6, wherein the IB weight equivalents areprovided.

TABLE 6 mg/unit dose Ingredient 60 mg Compound IB 73.95 MicrocrystallineCellulose 114.36 Croscarmellose sodium 10.85 Sodium starch glycolate10.85 Fumed Silica 0.65 Stearic acid 4.34 Total Fill Weight 217.00

In another aspect, the invention is directed to a pharmaceuticalcomposition comprising compound I, IA, or IB admixed with less than 100ppm 6,7-dimethoxy-quinoline-4-ol, the structure of which is

and a pharmaceutically acceptable carrier.

There are many different aspects and embodiments of the disclosuredescribed herein, and each aspect and each embodiment is non-limiting inregard to the scope of the disclosure. The terms “aspects” and“embodiments” are meant to be non-limiting regardless of where the terms“aspect” or “embodiment” appears in this specification. The transitionalterm “comprising,” as used herein, which is synonymous with “including,”“containing,” or “characterized by,” is inclusive or open-ended and doesnot exclude additional, unrecited elements.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

As used herein, the following words and phrases are generally intendedto have the meanings as set forth below, except to the extent that thecontext in which they are used indicates otherwise or they are expresslydefined to mean something different.

The word “can” is used in a non-limiting sense and in contradistinctionto the word “must” Thus, for example, in many aspects of the invention acertain element is described as “can” having a specified identity, whichis meant to convey that the subject element is permitted to have thatidentity according to the invention but is not required to have it.

If a group “R” is depicted as “floating” on a ring system, then unlessotherwise defined, the substituent(s) “R.” can reside on any atom of thering system, assuming replacement of a depicted, implied, or expresslydefined hydrogen from one of the ring atoms, so long as a stablestructure is formed.

When there are more than one such depicted “floating” groups, such aswhere there are two groups; then, unless otherwise defined, the“floating” groups can reside on any atoms of the ring system, againassuming each replaces a depicted, implied, or expressly definedhydrogen on the ring.

“Pharmaceutically acceptable salts” include acid addition salts.

“Pharmaceutically acceptable acid addition salt” refers to those saltsthat retain the biological effectiveness of the free bases and that arenot biologically or otherwise undesirable, formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like, or mixtures thereof, as well as organicacids such as acetic acid, trifluoroacetic acid, propionic acid,glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid,succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid,cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid, and the like, or mixturesthereof.

“Essentially free” as used in the phrase “essentially free of processbyproducts or contaminants,” means that a compound or composition asdisclosed here in is admixed with 200 parts per million (ppm) or less ofsuch byproducts or contaminants.

The disclosure is further illustrated by the following examples, whichare not to be construed as limiting the disclosure in scope or spirit tothe specific procedures described in them. Unless specified otherwise,the starting materials and various intermediates may be obtained fromcommercial sources, prepared from commercially available organiccompounds, or prepared using well-known synthetic processes.

Processes

Aspect 1: Processes for Making Compounds of Formula I

Aspect (1) of the invention relates to a process of preparing a compoundof formula I:

or a pharmaceutically acceptable salt thereof, wherein:

X¹ is H, Br, Cl, or F;

X² is H, Br, Cl, or F;

n1 is 1-2; and

n2 is 1-2;

the process comprising:

contacting the compound of formula g(1) with reactant z(1) to yield thecompound of formula I:

The reaction is advantageously carried out under suitable reactionconditions. Non-limiting examples of suitable reaction conditionsinclude using basic conditions. Non-limiting examples of basicconditions that can be used in Aspect (1) include the use of inorganicbases, such as aqueous KOH, NaOH, K₂CO₃, Ne₂CO₃, K₃PO₄, Na₃PO₄, K₂HPO₄,Na₂HPO₄, and the like, or mixtures thereof. Other non-limiting examplesof suitable reaction conditions include using suitable solvents.Non-limiting examples of suitable solvents that can be used includewater miscible solvents, such as THF, acetone, ethanol, and the like, ormixtures thereof. Other non-limiting examples of suitable reactionconditions include using suitable temperatures. Suitable temperaturesthat may be used for the reaction include a temperature at a range fromabout 10° C. to about 30° C., or alternatively, at a range from about15° C. to about 28° C., or alternatively, at a range from about 20° C.to about 25° C. The product formed by the reaction is in the free baseform, and this free base form may be converted into a pharmaceuticallyacceptable salt thereof by processes known in the art. For example, thecompound of formula I can be converted to the L-malate salt by theaddition of L-malic acid and a suitable solvent.

Utilities of the compound of formula I are further described in WO2005/030140 A2 which is incorporated herein by reference.

Embodiments of Aspect (1) Part A

In another embodiment of Aspect (1), X¹ is Cl or F.

In another embodiment of Aspect (1), X² is Cl or F.

In another embodiment of Aspect (1), X¹ is F.

In another embodiment of Aspect (1), X² is F.

In another embodiment of Aspect (1), X¹ is H.

In another embodiment of Aspect (1), X² is H.

In another embodiment of Aspect (1), n1 is 1.

In another embodiment of Aspect (1), n2 is 1.

In another embodiment of Aspect (1), n1 is 2.

In another embodiment of Aspect (1), n2 is 2.

All compounds of formula I for Aspect (1) disclosed above include any ofthe disclosed alternative embodiments in Part A for each of X¹, X², a1or n2, in combination with any other of the disclosed alternativeembodiments in Part A for each of X¹, X², a1, or n2, as well as apharmaceutically acceptable salt of any such combination.

Embodiments of Aspect (1) Part B

In another embodiment of Aspect (1), n1 and n2 are each 1.

In another embodiment of Aspect (1), n1 and n2 are each 2.

In another embodiment of Aspect (1), a1 is 1; and n2 is 2.

In another embodiment of Aspect (1), n1 is 2 and n2 is 1.

In another embodiment of Aspect (1), X¹ is H; and X² is F.

In another embodiment of Aspect (1), X¹ is F; and X² is H.

In another embodiment of Aspect (1), X¹ and X² are each H.

In another embodiment of Aspect (1), X¹ and X² are each F.

In another embodiment of Aspect (1), X¹ is Cl; and X² is H.

In another embodiment of Aspect (1), X¹ is H; and X² is Cl.

In another embodiment of Aspect (1), X¹ and X² are each Cl.

In another embodiment of Aspect (1), X¹ is Cl; and X² is F.

In another embodiment of Aspect (1), X¹ is F; and X² is Cl.

Embodiments of Aspect (1) Part C

In an embodiment of Aspect (1), the compound of formula g(1) can be madeby reacting a compound of formula f(1) with reactant y(1) to yield thecompound of a 1):

wherein LG represents a leaving group, and each of X², and n2 are asdefined in Aspect (1), or as in any of the embodiments of Aspect (1)Part A. A non-limiting example of a leaving group includes a halo groupsuch as Cl, Br, or F. Various compounds of reactant y(1) arecommercially available, such as 2-fluoro-4-aminophenol and4-aminophenol. Also, the skilled artisan would be able to make anyvariation of reactant y(1) using commercially available startingmaterials and by using known techniques to modify these commerciallyavailable starting materials to yield various compounds within the scopeof reactant y(1).

The reaction in this embodiment is advantageously carried out undersuitable reaction conditions. Non-limiting examples of suitable reactionconditions include using suitable solvents such as polar solvents.Non-limiting examples of polar solvents that can be used includetetrahydrofuran (THF), dimethylacetamide (DMA), dimethylsulfoxide(DMSO), dimethylformamide (DMF), ethyl acetate, N-methyl pyrrolidone(NMP), propylene carbonate, and the like, or mixtures thereof. Inanother embodiment, the polar solvent is dimethylacetamide (DMA). Inanother embodiment, the polar solvent is dimethylsulfoxide (DMSO). Inanother embodiment, the polar solvent is dimethylformamide (DMF). Inanother embodiment, the polar solvent is ethyl acetate. In anotherembodiment, the polar solvent is N-methyl pyrrolidone (NMP). In anotherembodiment, the polar solvent is propylene carbonate. In anotherembodiment, the solvent is a mixture of solvents, such as a mixturecomprising THF and DMA.

The reactants f(1) and y(1) can be added together at a temperatureranging from about 10° C. to about 30° C., or alternatively, from about15° C. to about 28° C., or alternatively, from about 20° C. to about 25°C. The mixture is then heated to a temperature ranging from about 80° C.to about 125° C., or alternatively, from about 95° C. to about 110° C.,or alternatively, from about 100° C. to about 105° C., and the selectedtemperature is maintained until the reaction is complete.

Other non-limiting examples of suitable reaction conditions in this stepof Aspect (1) include the use of a suitable base, such as a metalhydroxide or a non-nucleophilic base. Examples of metal hydroxidesinclude sodium hydroxide or potassium hydroxide. Non-limiting examplesof non-nucleophilic bases that can be used include lithiumdiisopropylamide, lithium tetramethylpiperidide, and alkali metalalkoxides such as sodium tert-butoxide, potassium tert-butoxide,sodium-pentoxide, and the like, or mixtures thereof. Preferably, thebase is sodium tert-butoxide or sodium tert-pentoxide. In oneembodiment, the base is sodium tert-pentoxide. Typically the sodiumtert-pentoxide is commercially available as 35 weight percent solutionof base in tetrahydrofuran, or as a 95 weight percent solid reagent.Preferably, the sodium tert-pentoxide is a 95 weight percent solid.

Typically, approximately 1.1 to 3.0 molar equivalents of base are usedrelative the moles of f(1) that are used. More preferably, 1.3 to 25molar equivalents of base are used relative the moles of f(1) that areused. More preferably, 1.5 to 2.2 molar equivalents of base are usedrelative the moles of f(1) that are used. More preferably, 1.7 to 2.1molar equivalents of base are used relative the moles of f(1) that areused.

Typically, the amount of molar equivalents of amino phenol that are usedexceeds the molar equivalents of base that are used. In one embodiment,1.1 to 2 molar equivalents of amino phenol are used relative to themolar equivalents of base that are used.

Once the reaction is substantially complete, the reaction mixture can becooled to a temperature ranging from about 10° C. to about 25° C.Precooled water can be charged at a rate to maintain a temperature thatranges from about 5° C. to about 35° C. Alternatively, the precooledwater can be charged at a rate to maintain a temperature that rangesfrom about 10° C. to about 25° C. As a non-limiting example, theprecooled water can be at a temperature ranging from about 0° C. toabout 10° C. As another non-limiting example, the precooled water can beat a temperature ranging from about 2° C. to about 7° C. The precipitatecan be collected by filtration under standard conditions and purified bystandard purification techniques.

Embodiments of Aspect (1) Part D

In an embodiment of Aspect (1), the compound of formula f(1) can be madeby converting a compound of formula e(1) to the compound of formulaf(1):

wherein LG represents a leaving group. Non-limiting examples of leavinggroups that can be used include halo groups (e.g., Cl, Br, or F) thatcan be added by halogenating agents. Non-limiting examples ofhalogenating agents that can be used include chlorinating agents, suchas SOCl₂, SO₂Cl₂, COCl₂, PCl₃, POCl₃, and the like.

The reaction is advantageously carried out under suitable reactionconditions. Non-limiting examples of suitable reaction conditions inPart D of Aspect (1) include the use of suitable solvents. Non-limitingexample of suitable solvents that can be used during the halogenation ofthe compound of formula e(1) include a polar, aprotic solvent, such asCH₃CN, DMF, and the like, or mixtures thereof In other embodiments, thechlorination can be carried out using POCl₃ in acetonitrile, COCl₂ inDMF, or SOCl₂ in DMF. The addition of the chlorination agent isadvantageously carried out at a temperature ranging from about 60° C. toabout 90° C. In another embodiment, the addition of the chlorinationagent can be carried out at a temperature ranging from about 70° C. toabout 85° C. In another embodiment, the addition of the chlorinationagent can be carried out at a temperature ranging from about 74° C. toabout 80° C. The product can then be collected by filtration andpurified using standard techniques.

Embodiments of Aspect (1) Part E

In an embodiment of Aspect (1), reactant z(1) can be made by reactingreactant z(1a) with a chlorinating agent to yield reactant z(1):

wherein X¹ is Br, Cl, or F; and n1 is 1-2. Compounds of reactant z(1a)can be made according to the process described in Example 25 of WO2005/030140 A2, and the skilled artisan would be able to make anynecessary substitutions using commercially available starting materialsto come up with various compounds within the scope of reactant z(1a).Example 25 in WO 2005/030140 A2 is incorporated herein by reference.

The reaction is advantageously carried out under suitable reactionconditions. Non-limiting examples of suitable reaction conditionsinclude using a chlorinating agent such as POCl₃, oxalyl chloride, andthe like. In another embodiment, oxalyl chloride is used as achlorinating agent. Non-limiting examples of suitable reactionconditions include carrying out the reaction at a temperature in therange from about 0° C. to about 25° C., or alternatively at atemperature in the range from about 5° C. to about 20° C. Othernon-limiting examples of suitable reaction conditions include carryingout the reaction in a suitable solvent. Non-limiting examples ofsuitable solvents that can be used include polar aprotic solvents, suchas halogenated hydrocarbons (e.g., dichloromethane and chloroform),ethers (e.g., Et₂O), dioxane, tetrahydrofuran (THF) containing catalyticDMF, and the like, or mixtures thereof. The resulting solutioncontaining reactant z(1) can be used, without further processing, tomake the compound of formula I.

Other Embodiments of Aspect (1)

In another embodiment of Aspect (1), the compound of formula I is acompound of formula IA-1:

or a pharmaceutically acceptable salt thereof, wherein:

X¹ is H, Cl, Br, or F; and X² is H, Cl, Br, or F. Compound IA can be inthe free base form or it can converted to a pharmaceutically acceptablesalt thereof. Accordingly, compound IA can be converted to its L-malatesalt by the addition of L-malic acid and a suitable solvent

In another embodiment of Part D of Aspect (1), the compound of formulae(1) is compound e(2):

and the compound of formula f(1) is compound f(2):

In another embodiment of Part C of Aspect (1), the compound of formula(1) is compound f(2):

reactant y(1) is reactant (y)(2):

wherein X² is hydrogen or fluoro; and

the compound of formula g(1) is of formula g(2):

In a further embodiment, the reaction employs a non-nucleophilic base.In a further embodiment, the non-nucelophilic base is an alkali metalalkoxide; and the reaction is carried out in a polar solvent. In afurther embodiment, the alkali metal alkoxide is sodium tert-butoxide,and the polar solvent is DMA.

In another embodiment of Part C of Aspect (1), the compound of formulaf(1) is compound f(2):

reactant y(1) is reactant (y)(3):

wherein X² is hydrogen or fluoro; and

-   the compound of formula g(1) is compound g(3):

In another embodiment of Aspect (1) of this disclosure, the compound offormula g(1) is compound g(3):

reactant z(1) is reactant (z)(2):

andthe compound of formula I is compound IA:

In a further embodiment, the reaction is carried out in the presence ofan inorganic base. In a further embodiment, the inorganic base is K₂CO₃,and the solvent employed in this reaction is a combination of THF andH₂O.

In another embodiment of Aspect (1) of this disclosure, X¹ and X² foreach of formula g(1) and reactant z(1) are each selected from Cl or F.In another embodiment, X¹ and X² for each of formula g(2), and reactantz(1) are both F.

The compound of formula f(2),or a pharmaceutically acceptable saltthereof; can be made by converting the compound of formula e(2) to acompound of formula f(2) with a chlorinating agent in a suitablesolvent:

The compound of formula f(2) can be in its free base form or convertedto a pharmaceutically acceptable salt thereof. The reaction conditionsthat can be used in this aspect include any of the reaction conditionsdisclosed in Part E of Aspect (1).Aspect 2: Processes for Making Compounds of Formula g(2)

Aspect (2) of the disclosure relates to a process of preparing compoundg(2):

or a pharmaceutically acceptable salt thereof; the process comprisingreacting compound f(2) with reactant y(3) under basic conditions (e.g.,using 2,6-lutidine) in an appropriate solvent to yield compound g(3):

The reaction conditions that can be used in this aspect include any ofthe reaction conditions disclosed in Part C of Aspect (1).

Alternative reaction conditions that can be used in this aspect includeany of the reaction conditions disclosed in Parts C and D of Aspect (1).

Aspect 3: Processes for Making Compounds of IB

As indicated above, in one aspect, the invention provides a process forpreparing compound IB:

from compound IA:comprising:

-   -   (a) heating and agitating a mixture comprising compound IA and        L-malic acid, methylethyl ketone, and water;    -   (b) cooling the mixture;    -   (c) vacuum distilling the mixture successively; and    -   (d) isolating the compound of IB by filtration.

In one embodiment of this aspect, compound IA is admixed with asufficient amount of L-malic acid in a methylethyl ketone (MEK)/water(1:1) mixture. Alternatively, L-malic acid is added as a solution inwater to a mixture of compound IA in methyl ethyl ketone. Generally theamount of L-malic is greater than 1 molar equivalent relative tocompound IA. The mixture of compound IA and L-malic acid in MEK/water isheated at about 40-70° C., and preferably at about 50-60° C., and morepreferably at about 55-60° C. with agitation, such as by stirring or thelike, for about 1 to about 5 hours. At the end of the heating, themixture is optionally clarified by filtering to give a clear solution.The resulting clear solution is then vacuum distilled from 1 to about 5times at 150 to 200 mm Hg and a maximum jacket temperature of 55° C. toprovide the desired crystalline compound of IB.

In one embodiment, L-malic acid is charged as a solution in water tocompound IA. Generally the amount of L-malic is greater than 1 molarequivalent relative to compound IA. The mixture of compound IA andL-malic acid in MEK/water is heated at about 40-70° C., and preferablyat about 50-60° C., and more preferably at about 55-60° C. withagitation, such as by stirring or the like, for about 1 to about 5hours. At the end of the heating, the mixture is optionally clarified byfiltering to give a clear solution which is at a temperature of about30-40° C., and more preferably at a temperature of about 33-37° C. Thisclear solution is optionally seeded to facilitate crystallization. Afterseeding, the resulting mixture is vacuum distilled as provided above.

In one embodiment, compound IB is in the N-1 form. In anotherembodiment, compound IB is in the N-2 form. In another embodiment,compound IB is a mixture of the N-1 form and the N-2 form. Processes forpreparing the N-1 and N-2 forms of compound IB are disclosed in WO2010/083414 (PCT/US2010021194), the entire contents of which areincorporated herein by reference.

In another embodiment, the disclosure relates to compound IA or IBadmixed with 100 ppm or less of 6,7-dimethoxy-quinoline-4-ol. In oneembodiment, the compound is admixed with 50 ppm or less of6,7-dimethoxy-quinoline-4-ol. In another embodiment, the compound isadmixed with 25 ppm or less of 6,7-dimethoxy-quinoline-4-ol. In anotherembodiment, the compound is admixed with 10 ppm or less of6,7-dimethoxy-quinoline-4-ol. In another embodiment, the compound isadmixed with 5 ppm or less of 6,7-dimethoxy-quinoline-4-ol. In anotherembodiment, the compound is admixed with 2.5 ppm or less of6,7-dimethoxy-quinoline-4-ol.

In another embodiment, the disclosure relates to compound IA admixedwith 100 ppm or less of 6,7-dimethoxy-quinoline-4-ol. In one embodiment,the compound is admixed with 50 ppm or less of6,7-dimethoxy-quinoline-4-ol. In another embodiment, the compound isadmixed with 25 ppm or less of 6,7-dimethoxy-quinoline-4-ol. In anotherembodiment, the compound is admixed with 10 ppm or less of6,7-dimethoxy-quinoline-4-ol. In another embodiment, the compound isadmixed with 5 ppm or less of 6,7-dimethoxy-quinoline-4-ol. In anotherembodiment, the compound is admixed with 2.5 ppm or less of6,7-dimethoxy-quinoline-4-ol.

In another embodiment, the disclosure relates to compound IB admixedwith 100 ppm or less of 6,7-dimethoxy-quinoline-4-ol. In one embodiment,the compound is admixed with 50 ppm or less of6,7-dimethoxy-quinoline-4-ol. In another embodiment, the compound isadmixed with 25 ppm or less of 6,7-dimethoxy-quinoline-4-ol. In anotherembodiment, the compound is admixed with 10 ppm or less of6,7-dimethoxy-quinoline-4-ol. In another embodiment, the compound isadmixed with 5 ppm or less of 6,7-dimethoxy-quinoline-4-ol. In anotherembodiment, the compound is admixed with 2.5 ppm or less of6,7-dimethoxy-quinoline-4-ol.

In another embodiment, the disclosure relates to compound IB in the N-1form admixed with 100 ppm or less of 6,7-dimethoxy-quinoline-4-ol. Inone embodiment, the compound is admixed with 50 ppm or less of6,7-dimethoxy-quinoline-4-ol. In another embodiment, the compound isadmixed with 25 ppm or less of 6,7-dimethoxy-quinoline-4-ol. In anotherembodiment, the compound is admixed with 10 ppm or less of6,7-dimethoxy-quinoline-4-ol. In another embodiment, the compound isadmixed with 5 ppm or less of 6,7-dimethoxy-quinoline-4-ol. In anotherembodiment, the compound is admixed with 2.5 ppm or less of6,7-dimethoxy-quinoline-4-ol.

In another embodiment, the disclosure relates to compound IB in the N-2form admixed with 100 ppm or less of 6,7-dimethoxy-quinoline-4-ol. Inone embodiment, the compound is admixed with 50 ppm or less of6,7-dimethoxy-quinoline-4-ol. In another embodiment, the compound isadmixed with 25 ppm or less of 6,7-dimethoxy-quinoline-4-ol. In anotherembodiment, the compound is admixed with 10 ppm or less of6,7-dimethoxy-quinoline-4-ol. In another embodiment, the compound isadmixed with 5 ppm or less of 6,7-dimethoxy-quinoline-4-ol. In anotherembodiment, the compound is admixed with 2.5 ppm or less of6,7-dimethoxy-quinoline-4-ol.

In another embodiment, the disclosure relates to compound IB as amixture of the N-1 form and the N-2 form admixed with 100 ppm or less of6,7-dimethoxy-quinoline-4-ol. In one embodiment, the compound is admixedwith 50 ppm or less of 6,7-dimethoxy-quinoline-4-ol. In anotherembodiment, the compound is admixed with 25 ppm or less of6,7-dimethoxy-quinoline-4-ol. In another embodiment, the compound isadmixed with 10 ppm or less of 6,7-dimethoxy-quinoline-4-ol. In anotherembodiment, the compound is admixed with 5 ppm or less of6,7-dimethoxy-quinoline-4-ol. In another embodiment, the compound isadmixed with 2.5 ppm or less of 6,7-dimethoxy-quinoline-4-ol.

Pharmaceutical Compositions

In another embodiment, the disclosure relates to a pharmaceuticalcomposition comprising Compound I, IA, or IB. Various carriers used informulating pharmaceutically acceptable compositions and knowntechniques for their bulk preparation and subsequent production intounit dosage forms are employed to make the pharmaceutical compositionsdisclosed herein and are described in Remington: The Science andPractice of Pharmacy, 21st edition, 2005, ed. D. B. Troy, LippincottWilliams & Wilkins, Philadelphia, and Encyclopedist of PharmaceuticalTechnology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, MarcelDekker, New York. The amount of carriers and excipients used in acomposition can be varied proportionally according to the amount ofactive ingredient used (that is, Compound I, IA or IB).

In one embodiment, the pharmaceutical composition is a tablet.

In another embodiment, the pharmaceutical composition is a capsule.

In another embodiment, the pharmaceutical composition comprises CompoundIA.

In another embodiment, the pharmaceutical composition comprises CompoundIB.

In another embodiment, the pharmaceutical composition comprises CompoundIB. as the N-1 polymorph.

In another embodiment, the pharmaceutical composition comprises CompoundIB as the N-2 polymorph.

In another embodiment, the pharmaceutical composition comprises CompoundIB as a mixture of the N-1 form and the N-2 form.

In another embodiment, the disclosure relates to a pharmaceuticalcomposition comprising Compound IA or IB; one or more fillers; one ormore disintergrants; one or more glidants; and one or more lubricants.

In this embodiment, the filter comprises microcrystalline cellulose.

In this embodiment, the disintegrant comprises croscarmellose sodium.

In this embodiment, the disintegrant comprises croscarmellose sodium andsodium starch glycolate.

In this embodiment, the glidant comprises fumed silica.

In this embodiment, the lubricant comprises stearic acid.

In another embodiment, the disclosure relates to a pharmaceuticalcomposition comprising Compound IA or IB; microcrystalline cellulose;lactose; hydroxypropyl cellulose; croscarmellose sodium; colloidalsilicon dioxide; and magnesium stearate.

In another embodiment, the disclosure relates to a pharmaceuticalcomposition comprising Compound IA or IB; microcrystalline cellulose;hydroxypropyl cellulose; a surfactant; croscarmellose sodium; colloidalsilicon dioxide; and magnesium stearate.

In another embodiment, the disclosure relates to a pharmaceuticalcomposition comprising Compound IA or IB; microcrystalline cellulose;croscarmellose sodium; fumed silica; and stearic acid.

In another embodiment, the disclosure relates to a pharmaceuticalcomposition comprising Compound IA or IB; microcrystalline cellulose;anhydrous lactose; hydroxypropyl cellulose; croscarmellose sodium;silicon dioxide; and magnesium stearate.

In another embodiment, the disclosure relates to a pharmaceuticalcomposition comprising Compound IA or IB; microcrystalline cellulose;anhydrous lactose; hydroxypropyl cellulose; a surfactant; croscarmellosesodium; silicon dioxide; and magnesium stearate.

In another aspect, the disclosure provides a pharmaceutical compositionaccording to Tables 1, 2, 2A, 3, 4, 5, and 6 as provided above. Thecompositions are prepared according to methods available to the skilledartisan. For example, the Tablet formulations are prepared by combining,blending, and compacting the components of the tablet compositions. Thecapsule compositions are prepared by combining and blending thecomponents and then placing the blend in a gelatin capsule.

For example, the 25 mg capsules (Table 3, 10 percent drug loadformulation) are prepared as follows. The drug substance is delumpedthrough a mill. The delumped drug substance is then co-screened with anequal volume Prosolv HD90. The excipients, except for stearic acid, arescreened and charged to a blender along with the co-screened drugsubstance. The mixture is blended in a V-Blender. This process isrepeated to manufacture a second sublot of unlubricated blend. The twosublets are then combined together in a V-blender and lubricated withstearic acid which has been co-screened with an equal volume ofunlubricated blend. The final blend is then encapsulated into opaque,size 1 gelatin capsules using an automated capsule filling machine. Thecapsules are then weight sorted through an automatic weight sorter.

The 100-mg capsules (Table 4, 50% drug load formulation) aremanufactured in two equal sublets of 5 kg of blend which are combinedprior to lubricant blend The drug substance is delumped through a mill.The excipients, except for stearic acid, are screened and charged to themixer along with the delumped drug substance. The mixture is blendedwith a high shear mixer. The process is repeated to manufacture a secondsublot of unlubricated blend. The final blend is then encapsulated intoSwedish oraopaque, size 1 gelatin capsules using an automated capsulefilling machine. The capsuare then weight sorted through an automaticweight sorter.

The 50 and 60 mg capsules (Tables 5 and 6) are prepared in a similarfashion as the 25 and 100 mg capsules.

In another aspect, the disclosure relates to a pharmaceuticalcomposition comprising a compound of Formula IA or IB and apharmaceutically acceptable carrier admixed with less than 100 ppm of6,7-dimethoxy-quinoline-4-ol. 6,7-dimethoxy-quinoline-4-ol, thestructure of which is

can be used as reagent e(1) to make chloride f(1) and is a byproductthat may form during the synthesis of Compound IA or IB. Minimizing theconcentration of contaminants or byproducts such as6,7-dimethoxy-quinoline-4-ol in pharmaceutical compositions destined forhuman administration is desirable.

In one embodiment, the pharmaceutical composition as defined in any ofthe previous embodiments (for example, the pharmaceutical composition ofTables 1, 2, 2A, 3, 4, 5, and 6) is admixed with 100 ppm6,7-dimethoxy-quinoline-4-ol.

In another embodiment, the pharmaceutical composition as defined in anyof the previous embodiments is admixed with 50 ppm6,7-dimethoxy-quinoline-4-ol.

In another embodiment, the pharmaceutical composition as defined in anyof the previous embodiments is admixed with 25 ppm6,7-dimethoxy-quinoline-4-ol.

In another embodiment, the pharmaceutical composition as defined in anyof the previous embodiments is admixed with 15 ppm6,7-dimethoxy-quinoline-4-ol.

In another embodiment, the pharmaceutical composition as defined in anyof the previous embodiments is admixed with 10 ppm6,7-dimethoxy-quinoline-4-ol.

In another embodiment, the pharmaceutical composition as defined in anyof the previous embodiments is admixed with 5 ppm6,7-dimethoxy-quinoline-4-ol.

In another embodiment, the pharmaceutical composition as defined in anyof the previous embodiments is admixed with 2.5 ppm6,7-dimethoxy-quinoline-4-ol.

In another embodiment, the disclosure relates to a pharmaceuticalcomposition comprising Compound IA or IB; one or more fillers; one ormore disintergrants; one or more glidants; and one or more lubricantsadmixed with 100 ppm or less 6,7-dimethoxy-quinoline-4-ol.

In this embodiment, the filler comprises microcrystalline cellulose.

In this embodiment, the disintegrant comprises croscarmellose sodium.

In this embodiment, the disintegrant comprises croscarmellose sodium andsodium starch glycolate.

In this embodiment, the glidant comprises fumed silica.

In this embodiment, the lubricant comprises stearic acid.

In another embodiment, the disclosure relates to a pharmaceuticalcomposition comprising Compound IA or IB; microcrystalline cellulose;croscarmellose sodium; fumed silica; and stearic acid; admixed with 100ppm or less of 6,7-dimethoxy-quinoline-4-ol. In one embodiment of thisembodiment, the composition is admixed with 50 ppm or less of6,7-dimethoxy-quinoline-4-ol. In another embodiment of this embodiment,the composition is admixed with 25 ppm or less of6,7-dimethoxy-quinoline-4-ol. In another embodiment of this embodiment,the composition is admixed with 10 ppm or less of6,7-dimethoxy-quinoline-4-ol. In another embodiment of this embodiment,the composition is admixed with 5 ppm or less of6,7-dimethoxy-quinoline-4-ol. In another embodiment of this embodiment,the composition is admixed with 2.5 ppm or less of6,7-dimethoxy-quinoline-4-ol.

In another embodiment, the disclosure relates to a pharmaceuticalcomposition comprising Compound IA or IB; microcrystalline cellulose;anhydrous lactose; hydroxypropyl cellulose; a surfactant; croscarmellosesodium; silicon dioxide; and magnesium stearate; admixed with 100 ppm orless of 6,7-dimethoxy-quinoline-4-ol. In one embodiment of thisembodiment, the composition is admixed with 50 ppm or less of6,7-dimethoxy-quinoline-4-ol. In another embodiment of this embodiment,the composition is admixed with 25 ppm or less of6,7-dimethoxy-quinoline-4-ol. In another embodiment of this embodiment,the composition is admixed with 10 ppm or less of6,7-dimethoxy-quinoline-4-ol. In another embodiment of this embodiment,the composition is admixed with 5 ppm or less of6,7-dimethoxy-quinoline-4-ol. In another embodiment of this embodiment,the composition is admixed with 2.5 ppm or less of6,7-dimethoxy-quinoline-4-ol.

In another embodiment, the disclosure relates to a pharmaceuticalcomposition comprising Compound IA or IB; microcrystalline cellulose;croscarmellose sodium; fumed silica; and stearic acid; admixed with 100ppm or less of 6,7-dimethoxy-quinoline-4-ol. In one embodiment of thisembodiment, the composition is admixed with 50 ppm or less of6,7-dimethoxy-quinoline-4-ol. In another embodiment of this embodiment,the composition is admixed with 25 ppm or less of6,7-dimethoxy-quinoline-4-ol. In another embodiment of this embodiment,the composition is admixed with 10 ppm or less of6,7-dimethoxy-quinoline-4-ol. In another embodiment of this embodiment,the composition is admixed with 5 ppm or less of6,7-dimethoxy-quinoline-4-ol. In another embodiment of this embodiment,the composition is admixed with 2.5 ppm or less of6,7-dimethoxy-quinoline-4-ol.

EXAMPLES

The invention is illustrated further by the following examples in Scheme1 and the description thereof, which are not to be construed as limitingthe invention in scope or spirit to the specific procedures described inthem. Those having skill in the art will recognize that the startingmaterials may be varied and additional steps employed to producecompounds encompassed by the invention, as demonstrated by the followingexamples. Those skilled in the art will also recognize that it may benecessary to utilize different solvents or reagents to achieve some ofthe above transformations. Unless otherwise specified, all reagents andsolvents are of standard commercial grade and are used without furtherpurification. The appropriate atmosphere to run the reaction under, forexample, air, nitrogen, hydrogen, argon, and the like, will be apparentto those skilled in the art.

Preparation ofN4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideand the (L)-malate salt thereof.

A synthetic route that can be used for the preparation ofN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-fluorophenyl)cyclopropane-1,1-dicarboxamideand the (L)-malate salt thereof is depicted in FIG. 1:

Preparation of 4-Chloro-6,7-dimethoxy-quinoline

A reactor was charged sequentially with 6,7-dimethoxy-quinoline-4-ol(47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heatedto approximately 60° C., and phosphorus oxychloride (POCl₃, 130.6 kg)was added. After the addition of POCl₃, the temperature of the reactionmixture was raised to approximately 77° C. The reaction was deemedcomplete (approximately 13 hours) when less than 3% of the startingmaterial remained (in-process high-performance liquid chromatography[HPLC] analysis). The reaction mixture was cooled to approximately 2-7°C. and then quenched into a chilled solution of dichloromethane (DCM,482.8 kg), 26% NH₄OH (251.3 kg), and water (900 L). The resultingmixture was warmed to approximately 20-25° C., and phases wereseparated. The organic phase was filtered through a bed of AW hyflosuper-cel NF (Celite; 5.4 kg) and the filter bed was washed with DCM(118.9 kg). The combined organic phase was washed with brine (282.9 kg)and mixed with water (120 L). The phases were separated and the organicphase was concentrated by vacuum distillation with the removal ofsolvent (approximately 95 L residual volume). DCM (686.5 kg) was chargedto the reactor containing organic phase and concentrated by vacuumdistillation with the removal of solvent (approximately 90 L residualvolume). Methyl t-butyl ether (MTBE, 226.0 kg) was then charged and thetemperature of the mixture was adjusted to −20 to −25° C. and held for2.5 hours resulting in solid precipitate which was then filtered andwashed with n-heptane (92.0 kg), and dried on a filter at approximately25° C. under nitrogen to afford the title compound. (35.6 kg).

Preparation of 4-(6.7-dimethoxy-quinoline-4-yloxy)-phenylamine

4-Aminophenol (24.4 kg) dissolved in N,N-dimethylacetamide (DMA, 184.3kg) was charged to a reactor containing 4-chloro-6,7-dimethoxyquinoline(35.3 kg), sodium t-butoxide (21.4 kg) and DMA (167.2 kg) at 20-25° C.This mixture was then heated to 100-105° C. for approximately 13 hours.After the reaction was deemed complete as determined using in-processHPLC analysis (<2% starting material remaining), the reactor contentswere cooled at 15 to 20° C. and water (pre-cooled, 2 to 7° VC., 587 L)charged at a rate to maintain 15 to 30° C. temperature. The resultingsolid precipitate was filtered, washed with a mixture of water (47 L)and DMA (89.1 kg) and finally with water (214 L). The filter cake wasthen dried at approximately 25° C. on filter to yield crude4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (59.4 kg wet, 41.6 kgdry calculated based on LOD). Crude4-(6,7-dimethoxy-quinoline-4-yloxyyphenylamine was refluxed(approximately 75° C.) in a mixture of tetrahydrofuran (THF, 211.4 kg)and DMA (108.8 kg) for approximately 1 hour and then cooled to 0-5° C.and aged for approximately 1 h after which time the solid was filtered,washed with THF (147.6 kg) and dried on a filter under vacuum atapproximately 25° C. to yield4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (34.0 kg).

Alternative Preparation of4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine

4-chloro-6,7-dimethoxyquinoline (34.8 kg) and 4-aminophenol (30.8 kg)and sodium tern pentoxide (1.8 equivalents) 88.7 kg, 35 wt percent inTHF) were charged to a reactor, followed by N,N-dimethylacetamide (DMA,293.3 kg). This mixture was then heated to 105-115° C. for approximately9 hours. After the reaction was deemed complete as determined usingin-process HPLC analysis (<2% starting material remaining), the reactorcontents were cooled at 15 to 25° C. and water (315 kg) was added over atwo hour period while maintaining the temperature between 20 and 30° C.The reaction mixture was then agitated for an additional hour at 20 to5° C. The crude product was collected by filtration and washed with amixture of 88 kg water and 82.1 kg DMA, followed by 175 kg water. Theproduct was dried on a filter drier for 53 hours. The LOD showed lessthan 1% w/w.

In an alternative procedure, 1.6 equivalents of sodium tert-pentoxidewere used and the reaction temperature was increased from 110-120° C. Inaddition, the cool down temperature was increased to 35-40° C. and thestarting temperature of the water addition was adjusted to 35-40° C.,with an allowed exotherm to 45° C.

Preparation of 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid

Triethylamine (19.5 kg) was added to a cooled (approximately 5 C)solution of cyclopropane-1,1-dicarboxylic acid (24.7 kg) in THF (89.6kg) at a rate such that the batch temperature did not exceed 5° C. Thesolution was stirred for approximately 1.3 hours, and then thionylchloride (23.1 kg) was added, keeping the batch temperature below 10° C.When the addition was complete, the solution was stirred forapproximately 4 h keeping temperature below 10° C. A solution of4-fluoroaniline (18.0 kg) in THF (33.1 kg) was then added at a rate suchthat the batch temperature did not exceed 10° C. The mixture was stirredfor approximately 10 hours after which the reaction was deemed complete.The reaction mixture was then diluted with isopropyl acetate (218.1 kg).This solution was washed sequentially with aqueous sodium hydroxide(10.4 kg, 50% dissolved in 119 L of water) further diluted with water(415 L), then with water (100 L) and finally with aqueous sodiumchloride (20.0 kg dissolved in 100 L of water). The organic solution wasconcentrated by vacuum distillation (100 L residual volume) below 40° C.followed by the addition of n-heptane (171.4 kg), which resulted in theprecipitation of solid. The solid was recovered by filtration and washedwith n-Heptane (102.4 kg) resulting in wet crude,1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (29.0 kg). Thecrude, 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid wasdissolved in methanol (139.7 kg) at approximately 25° C. followed by theaddition of water (320 L) resulting in slurry which was recovered byfiltration, washed sequentially with water (20 L) and n-heptane (103.1kg) and then dried on the filter at approximately 25° C. under nitrogento afford the title compound (25.4 kg).

Preparation of 1-(4-Fluoro-phenylcarbamoyl-cyclopropanecarbonyl chloride

Oxalyl chloride (12.6 kg) was added to a solution of1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (22.8 kg) in amixture of THF (96.1 kg) and N,N-dimethylformamide (DMF; 0.23 kg) at arate such that the batch temperature did not exceed 25° C. This solutionwas used in the next step without further processing.

Alternative Preparation of1-(4-Fluoro-phenylcarbamoyl)-cyclopronanecarbonyl chloride

A reactor was charged with1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (35 kg), 344 gDMF, and 175kg THF. The reaction mixture was adjusted to 12-17° C. andthen to the reaction mixture was charged 19.9 kg of oxalyl chloride overa period of I hour. The reaction mixture was left stirring at 12-17° C.for 3 to 8 hours. This solution was used in the next step withoutfurther processing.

Preparation of cyclopronane-1,1-dicarboxylic acid[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide(4-fluoro-phenyl-amide (Compound IA)

The solution from the previous step containing1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride was added toa mixture of compound 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine(23.5 kg) and potassium carbonate (31.9 kg) in THF (245.7 kg) and water(116 L) at a rate such that the batch temperature did not exceed 30° C.When the reaction was complete (in approximately 20 minutes), water (653L) was added. The mixture was stirred at 20-25° C. for approximately 10hours, which resulted in the precipitation of the product. The productwas recovered by filtration, washed with a pre-made solution of THF(68.6 kg) and water (256 L), and dried first on a filter under nitrogenat approximately 25° C. and then at approximately 45° C. under vacuum toafford the title compound (41.0 kg, 38.1 kg, calculated based on LOD).

Alternative Preparation of cyclonronane-1.1-dicarboxylic acid[4-(6,7-dimethoxy-quinoline-4-yloxyl-phenyl]-amide(4-fluoro-Rhenyl-amide

A reactor was charged with4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (35.7 kg, 1 equivalent),followed by 412.9 kg THF. To the reaction mixture was charged a solutionof 48.3 K₂CO₃ in 169 kg water. The acid chloride solution of describedin the Alternative Preparation of1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride above wastransferred to the reactor containing4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine while maintaining thetemperature between 20-30° C. over a minimum of two hours. The reactionmixture was stirred at 20-25° C. for a minimum of three hours. Thereaction temperature was then adjusted to 30-25° C. and the mixture wasagitated. The agitation was stopped and the phases of the mixture wereallowed to separate. The lower aqueous phase was removed and discarded.To the remaining upper organic phase was added 804 kg water. Thereaction was left stirring at 15-25° C. for a minimum of 16 hours.

The product precipitated. The product was filtered and washed with amixture of 179 kg water and 157.9 THF in two portions. The crude productwas dried under a vacuum for at least two hours. The dried product wasthen taken up in 285.1 kg THF. The resulting suspension was transferredto reaction vessel and agitated until the suspension became a clear(dissolved) solution, which required heating to 30-35° C. forapproximately 30 minutes. 456 kg water was then added to the solution,as well as 20 kg SDAG-1 ethanol (ethanol denatured with methanol overtwo hours. The mixture was agitated at 15-25° C. for at least 16 hours.The product was filtered and washed with a mixture of 143 kg water and126.7 THF in two portions. The product was dried at a maximumtemperature set point of 40° C.

In an alternative procedure, the reaction temperature during acidchloride formation was adjusted to 10-15° C. The recrystallizationtemperature was changed from 15-25° C. to 45-50° C. for 1 hour and thencooled to 15-25° C. over 2 hours.

Preparation of cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide, (L) malatesalt (Compound IB)

Cyclopropane-1,1-dicarboxylic acid[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]amide(4-fluoro-phenyl)-amide (1-5; 13.3 kg), L-malic acid (4.96 kg), methylethyl ketone (MEK; 188.6 kg) and water (37.3 kg) were charged to areactor and the mixture was heated to reflux (approximately 74° C.) forapproximately 2 hours. The reactor temperature was reduced to 50 to 55°C. and the reactor contents were filtered. These sequential stepsdescribed above were repeated two more times starting with similaramounts of 1-5 (13.3 kg), L-Malic acid (4.96 kg), MEK (198.6 kg) andwater (37.2 kg). The combined filtrate was azeotropically dried atatmospheric pressure using MEK (1133.2 kg) (approximate residual volume711 L; KF≤0.5% w/w) at approximately 74° C. The temperature of thereactor contents was reduced to 20 to 25° C. and held for approximately4 hours resulting in solid precipitate which was filtered, washed withMEK (448 kg) and dried under vacuum at 50° C. to afford the titlecompound (45.5 kg).

Alternative Preparation of cyclopropane-1,1-dicarboxylic acid[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide(4-fluoro-phenyl-amide. (L) malate salt

Cyclopropane-1,1-dicarboxylic acid[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide (47.9 kg), L-malic acid (17.2), 658.2 kg methylethyl ketone, and 129.1 kg water (37.3 kg) were charged to a reactor andthe mixture was heated 50-55° C. for approximately 1-3 hours, and thenat 55-60° C. for an addition al 4-5 hours. The mixture was clarified byfiltration through a 1 μm cartridge. The reactor temperature wasadjusted to 20-25° C. and vacuum distilled with a vacuum at 150-200 mmHg with a maximum jacket temperature of 55° C. to the volume range of558-731 L.

The vacuum distillation was performed two more times with the charge of380 kg and 380.2 kg methyl ethyl ketone, respectively. After the thirddistillation, the volume of the batch was adjusted to 18 v/w ofCyclopropane-1,1-dicarboxylic acid[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide by charging 159.9 kg methyl ethyl ketone to givea total volume of 880L. An addition al vacuum distillation was carriedout by adjusting 245.7 methyl ethyl ketone. The reaction mixture wasleft with moderate agitation at 20-25° C. for at least 24 hours. Theproduct was filtered and washed with 415.1 kg methyl ethyl ketone inthree portions. The product was dried under a vacuum with the jackettemperature set point at 45° C.

In an alternative procedure, the order of addition was changed so that asolution of 17.7 kg L-malic acid dissolved in 129.9 kg water was addedto Cyclopropane-1,1-dicarboxylic acid[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide (48.7 kg) in methyl ethyl ketone (673.3 kg).

Preparation of Compound IB, Form N-1

A solution was prepared by adding tetrahydrofuran (12 mL/g-bulk-LR(limiting reagent); 1.20 L) andN-(4-{[6,7-bis(methyloxy)-quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarborcamide,(100 g; 1.00 equiv; 100.00 g) and (L)-malic acid (1.2 equiv (molar);32.08 g) to a 1 L reactor. Water (0.5317 mL/g-bulk-LR; 53.17 mL) wasadded and the solution was heated to 60° C. and maintained at thattemperature for one hour until the solids were fully dissolved. Thesolution was passed through a Polish Filter.

At 60° C., acetonitrile (12 mL/g-bulk-LR; 1.20 L) was added over aperiod of 8 hours. The solution was held at 60° C. for 10 hours. Thesolution was then cooled to 20° C. and held for 1 hour. The solids werefiltered and washed with acetonitrile (12 mL/g-bulk-LR; 1.20 L). Thesolids were dried at 60° C. (25 mm Hg) for 6 hours to afford compound(I), Form N-1(108 g; 0.85 equivalent; 108.00 g; 85.22% yield) as a whitecrystalline solid.

Alternate Preparation of Compound IB, Form N-1

A solution was prepared with 190 mL tetrahydrofuran (110 mL), methylisobutyl ketone, and 29 mL water. Next, 20 mL of this solution weretransferred into an amber bottle, and then saturated by addingN-(4-{[6,7-bis(methyloxy)-quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(L)-malate until a thick slurry formed, and aging for at least 2 hourswith stirring at room temperature. The solids were removed by filtrationthrough a Buchner funnel, rendering a clear saturated solution.

Separately, a powder blend was made with known amounts of two batches ofcompound IB: (1) 300 mg of batch 1, which contained approximately 41%compound IB, Form N-1 and 59% compound IB, Form N-2 by Ramanspectroscopy analysis, and (2) 200 mg of batch 2, which had a XPRDpattern similar to compound E3, Form N-2.

The compound IB, Form N-1 and compound (I), Form N-2 powder blend wasadded into the saturated solution, and the slurry was aged undermagnetic stirring at room temperature for 25 days. The slurry was thensampled and filtered through a Buchner funnel to obtain 162 mg of wetcake. The wet cake was dried in a vacuum oven at 45° C. to afford 128 mgof crystalline compound IB in the N-1 form.

Preparation of Crystalline Compound IB Form N-2

Preparation of Crystalline Compound IB, Form N-2 Seed Crystals

A solution was prepared by combining 20 ml of acetone and 300 mg ofcompound IA(N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide)in a 25 ml screw capped vial. Next, 0.758 ml of a 0.79M (L)-malic acidstock solution was added to the vial with magnetic stirring. Thesolution was then left stirring for 24 hours at ambient temperature. Thesample was then suction filtered with 0.45 μm PTFE filter cartridge anddried in vacuo at ambient temperature overnight.

Preparation of Crystalline Compound IB, Form N-2.

To a reactor were addedN-(4-{[6,7-bis(methyloxy)-quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(48 g; 1.00 equiv; 48.00 g) and tetrahydrofuran (16.5 mL/g-bulk-LR;792.00 mL). The water content was adjusted to 1 wt % water. The solutionwas heated to 60° C. Once dissolved, the solution was passed through apolish filter to provide the first solution.

In a separate reactor, (L)-malic acid (1.2 equiv (molar); 15.40 g) wasdissolved into methyl isobutyl ketone (10 mL/g-bulk-LR; 480.00 mL) andtetrahydrofuran (1 mL/g-bulk-LR; 48.00 mL). Next, 50 mL of the (L)-malicacid solution was added to the first solution at 50° C. Seed crystalswere added (1%, 480 mg) and the malic acid solution was added at 50° C.dropwise via an addition funnel (1.3 ml/min over 3 hours). The slurrywas held at 50° C. for 18 hours and then was cooled to 25° C. over 30minutes. The solids were filtered, and washed with 20%tetrahydrofuran/methyl isobutyl ketone (10V, 480 mL). The solids weredried under vacuum at 60° C. for 5 hours to afford compound IB (55.7 g;0.92 equivalent; 55.70 g; 91.56% yield) as an off-white crystallinesolid.

Stability Studies of Pharmaceutical Compositions

The pharmaceutical capsule compositions of Tables 3 and 4 were preparedby mixing the ingredients according to processes known in the art.

TABLE 3 mg/unit Ingredient dose Compound IB (10% drug 25 load asCompound IA) Microcrystalline Cellulose 196.75 Croscarmellose sodium12.5 Sodium starch glycolate 12.5 Fumed Silica 0.75 Stearic acid 2.5Total Fill Weight 250

TABLE 4 mg/unit Ingredient dose Compound IB (50% drug 100 load asCompound IA) Silicified Microcrystalline 75.40 Cellulose Croscarmellosesodium 10.00 Sodium Starch Glycolate 10.00 Fumed silica 0.6 Stearic Acid4.0 Total Fill Weight 200

The capsule compositions were subjected to stability studies to monitorthe formation of 6,7-dimethoxy-quinoline-4-ol at various temperaturesand relative humidities over time. The results are summarized in Tables7A and 7B and Tables 8A and 8B.

TABLE 7A Stability of 25 Mg Capsules (Table 3) Bottle A1 Bottle A2Bottle A3 Bottle A4 Conditions PPM of 6,7-dimethoxy-quinoline-4-olInitial T = 0 25° C./60% RH 2 2 3 3 1 Month 25° C./60% RH 3 4 5 NA 30°C./75% RH 4 4 NA NA 40° C./75% RH 9 9 10 NA 3 Months 25° C./60% RH 5 5 7NA 30° C./75% RH 7 6 NA NA 40° C./75% RH 22 23 24 NA 6 Months 25° C./60%RH 6 6 7  7 (3M in blister) 30° C./75% RH 9 9 NA NA 40° C./75% RH 40 4443 27 (3M in blister) 9 Months 25° C./60% RH 7 7 9  8 (6M in blister)30° C./75% RH 13 12 NA NA 40° C./75% RH NA NA 68 60 (6M in blister) M =Months; NA = Not Applicable; RH = Relative Humidity; PPM = Parts perMillion. A portion of Bottle A4 was repackaged in a blister pack afterbeing stored in bottles for 3 months.

TABLE 7B Stability of 25 Mg Capsules (Table 3) Bottle B1 Bottle B BottleB3 Bottle B4 Conditions PPM of 6,7-dimethoxy-quinoline-4-ol Initial T =0 25° C./60% RH 3 1 2 2 1 Month 25° C./60% RH <2 <2 <2 NA 30° C./75% RH<2 <2 NA NA 40° C./75% RH 2 <2 <2 NA 3 Months 25° C./60% RH 2 <2 <2 NA30° C./75% RH 2 <2 NA NA 40° C./75% RH 3 <2 <2 NA 6 Months 25° C./60% RH<2 <2 <2 <2 (3M in blister) 30° C./75% RH 2 <2 NA NA 40° C./75% RH 4 <23   3 (3M in blister) 9 Months 25° C./60% RH <2 <2 <2 <2 (6M in blister)30° C./75% RH 3 <2 NA NA 40° C./75% RH NA NA 5   4 (6M in blister) Aportion of Bottle B4 was repackaged in a blister pack after being storedin bottles for 3 months.

TABLE 8A Stability of 100 Mg Capsules (Table 4) Bottle A1 Blister A2Bottle A3 Conditions PPM of 6,7-dimethoxy-quinoline-4-ol Initial T = 025° C./60% RH 4 4 6 1 Month 25° C./60% RH 4 4 6 30° C./75% RH 4 NA 6 40°C./75% RH 6 6 9 3 Months 25° C./60% RH 5 5 7 30° C./75% RH 6 NA 7 40°C./75% RH 10 10 12 6 Months 25° C./60% RH 5 5 30° C./75% RH 6 NA 40°C./75% RH 11 17 M = Months; NA = Not Applicable; RH = Relative Humidity;PPM = Parts per Million.

TABLE 8B Stability of 100 Mg Capsules (Table 4) Bottle B1 Blister B2Bottle B3 Conditions PPM of 6,7-dimetho-quinoline-4-o1 Initial T = 0 25°C./60% RH 1 1 2 1 Month 25° C./60% RH <2 <2 <2 30° C./75% RH <2 <2 2 40°C./75% RH <2 <2 2 3 Months 25° C./60% RH <2 <2 <2 30° C./75% RH <2 NA <240° C./75% RH <2 <2 2 6 Months 25° C./60% RH <2 <2 30° C./75% RH <2 NA40° C./75% RH 2 2 M = Months; NA = Not Applicable; RH = RelativeHumidity; PPM = Parts per Million.

The results summarized in Tables 7A and 7B and 8A and 8B indicate thatformation of 6,7-dimethoxy-quinoline-4-ol was minimized to 50 ppm orless over time in the capsule formulations.

The foregoing disclosure has been described in some detail by way ofillustration and example, for purposes of clarity and understanding. Theinvention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications can be made while remainingwithin the spirit and scope of the invention. It will be obvious to oneof skill in the art that changes and modifications can be practicedwithin the scope of the appended claims. Therefore, it is to beunderstood that the above description is intended to be illustrative andnot restrictive. The scope of the invention should, therefore, bedetermined not with reference to the above description, but shouldinstead be determined with reference to the following appended claims,along with the full scope of equivalents to which such claims areentitled. All references cited herein are incorporated by reference intheir entirety.

The invention claimed is:
 1. A process for preparing a compound offormula I:

or a pharmaceutically acceptable salt thereof, wherein: X¹ is H, Br, Cl,or F; X² is Br, Cl, or F; n1 is 1-2; and n2 is 1-2; the processcomprising: reacting a compound of formula f(1) with a reactant y(1) inthe presence of a non-nucleophilic base which is an alkali metalalkoxide to yield the compound of formula g(1):

wherein LG represents a leaving group; and contacting a compound offormula g(1) with a reactant z(1) to yield the compound of formula I:


2. The process according to claim 1, wherein the compound of formulaf(1) is made by converting a compound of formula e(1) to the compound offormula f(1):

wherein LG represents a leaving group.
 3. The process according to claim1, wherein reactant z(1) is made by reacting a reactant z(1a) with achlorinating agent to yield the reactant z(1):

wherein X¹ is Br, Cl, or F; and n1 is 1-2.
 4. The process according toclaim 1, wherein the compound of formula I is a compound of formulaIA-1:

or a pharmaceutically acceptable salt thereof, wherein: X¹ is H, Cl, Br,or F; and X² is Cl, Br, or F.
 5. The process according to claim 1,wherein the compound of formula f(1) is the compound f(2):

the reactant y(1) is a reactant (y)(2):

wherein X² is fluoro; and the compound of formula g(1) is a compound offormula g(2):


6. The process according to claim 1, wherein the reaction is carried outin a polar solvent.
 7. The process according to claim 6, wherein thealkali metal alkoxide is sodium tert-butoxide and the polar solvent isDMA.
 8. The process according to claim 6, wherein the alkali metalalkoxide is sodium tert-pentoxide, and the polar solvent is DMA.
 9. Theprocess according to claim 1, wherein the reaction is carried out in thepresence of an inorganic base.
 10. The process according to claim 9,wherein the inorganic base is K₂CO₃, and the reaction is carried out ina solvent comprising a combination of THF and H₂O.
 11. A process forpreparing a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein: X¹ is H, Br orCl; X² is H; n1 is 1-2; and n2 is 1-2; the process comprising: reactinga compound of formula f(1) with a reactant y(1) in the presence of anon-nucleophilic base which is an alkali metal alkoxide to yield thecompound of formula g(1):

wherein LG represents a leaving group; and contacting a compound offormula g(1) with a reactant z(1) to yield the compound of formula I:


12. The process according to claim 11, wherein the compound of formulaf(1) is made by converting a compound of formula e(1) to the compound offormula f(1):

wherein LG represents a leaving group.
 13. The process according toclaim 11, wherein reactant z(1) is made by reacting a reactant z(1a)with a chlorinating agent to yield the reactant z(1):

wherein X¹ is H, Br or Cl; and n1 is 1-2.
 14. The process according toclaim 11, wherein the compound of formula I is a compound of formulaIA-1:

or a pharmaceutically acceptable salt thereof, wherein: X¹ is H, Cl orBr; and X² is H.
 15. The process according to claim 11, wherein thecompound of formula f(1)

the reactant y(1) is a reactant (y)(2):

wherein X² is hydrogen; and the compound of formula g(1) is a compoundof formula g(2):


16. The process according to claim 11, wherein the reaction is carriedout in a polar solvent.
 17. The process according to claim 16, whereinthe alkali metal alkoxide is sodium tert-butoxide or sodiumtert-pentoxide, and the polar solvent is DMA.
 18. The process accordingto claim 11, wherein the reaction is carried out in the presence of aninorganic base.
 19. The process according to claim 18, wherein theinorganic base is K₂CO₃, and the reaction is carried out in a solventcomprising a combination of THF and H₂O.
 20. A process for preparing acompound of formula I:

or a pharmaceutically acceptable salt thereof, wherein: X¹ is F; X² isH; and n1 is 2; the process comprising: reacting a compound of formulaf(1) with a reactant y(1) in the presence of a non-nucleophilic basewhich is an alkali metal alkoxide to yield the compound of formula g(1):

wherein LG represents a leaving group; and contacting a compound offormula g(1) with a reactant z(1) to yield the compound of formula I: